Project Summary. This proposal details a training program for the development of the candidate's academic career in cancer biology. The candidate will use the dedicated period to consolidate and focus her independent research program. The candidate will be mentored by a leading cancer biologist, Dr. Harold Varmus, who has trained numerous productive scientists. The Memorial Sloan-Kettering Cancer Center will provide institutional support. Ample resources and multiple career development activities will be available to help the candidate to achieve her goals. The long-term goal is to achieve complete eradication of cancer cells by interfering with critical tumor oncogenes. The specific hypothesis is that tumor maintenance depends on multiple oncogenes. It is based on the observations that 1) multiple oncogenic mutations contribute to the malignant transformation of mammalian cells, 2) tumors depend on the continuous expression of the initiating oncogene, and regress in response to its inactivation, and 3) a number of residual cells are resistant to primary oncogene inactivation and are responsible for the relapse. Research will focus on Myc and Ras pathway oncogenes in tumor progression and maintenance, initially by using a mouse mammary tumor model system, followed by translation into a human cell system. The specific aims are to: 1. Establish mammary tumor models where the expression of a single or multiple oncogenes of the Myc and Ras pathways is regulated by doxycycline. 2. Evaluate tumor response to the inactivation of a secondary oncogene alone or of a combination of primary and secondary oncogenes. 3. Identify oncogenic mutations that may contribute to the resistance to oncogene inactivation and to tumor relapse. Relevance. The proposal addresses three questions directly relevant to human cancer: 1) Of all the mutant proteins found in a given tumor, how many have to be inactivated in order to eradicate the tumor? 2) Of all the mutations contributing to tumorigenesis, which are the most critical to interfere with in order to eradicate cancer? 3) what are the oncogenic partners of the common human oncogenes MYC and RAS?